Models for Assessing Drug Absorption and Metabolism

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Springer Science & Business Media, Aug 31, 1996 - Medical - 444 pages
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Pharmaceutical scientists in industry and academia will appreciate this single reference for its detailed experimental procedures for conducting biopharmaceutical studies. This well-illustrated guide allows them to establish, validate, and implement commonly used in situ and in vitro model systems. Chapters provide ready access to these methodologies for studies of the intestinal, buccal, nasal and respiratory, vaginal, ocular, and dermal epithelium as well as the endothelial and elimination barriers.
 

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Contents

General Principles in the Characterization and Use of Model Systems for Biopharmaceutical Studies
1
2 BIOLOGICAL BARRIERS TO DRUG DELIVERY
3
3 DESIRABLE CHARACTERISTICS OF A MODEL SYSTEM
4
4 CHARACTERIZATION OF MODEL SYSTEMS
5
5 APPLICATIONS TO PHARMACEUTICAL PROBLEMS
7
6 FUTURE DIRECTIONS
8
7 CONCLUSIONS
9
Methods for Evaluating Intestinal Permeability and Metabolism in Vitro
13
33 Mathematical Model
228
34 Estimation of Capillary Permeability
230
Kinetic Analysis of the Renal Tubular Secretion of Organic Anions and Cations by the MID Method Combined with a Mathematical Model
231
4 ADVANTAGES AND DISADVANTAGES OF THE IPK
233
REFERENCES
236
Brain Microvessel Endothelial Cell Culture Systems
239
2 METHODS
240
23 Brain Microvessel Isolation
241

2 METHODS
14
22 Tissue Preparation
17
23 Transport Studies
19
24 Metabolism Studies
21
3 APPLICATIONS FOR ABSORPTION AND METABOLISM
22
32 Evaluation of Formulation Approaches
24
33 Metabolism Studies
27
34 Discovery Screening
28
4 ADVANTAGES AND DISADVANTAGES OF TISSUE TECHNIQUES
29
REFERENCES
30
Cultured Intestinal Epithelial Cell Models
35
2 METHODS
36
23 Experimental Protocols
39
24 Calculations of Data
42
3 APPLICATIONS TO ABSORPTION AND METABOLISM STUDIES
45
32 Drug Metabolism
46
33 In Vitroin Vivo Correlations
47
4 ADVANTAGES AND DISADVANTAGES OVER OTHER METHODS
48
REFERENCES
49
Intestinal Rings and Isolated Intestinal Mucosal Cells
51
2 PREPARATION OF EVERTED RINGS OR ISOLATED EPITHELIAL CELLS
52
3 DEMONSTRATION OF FUNCTIONAL VIABILITY OF RINGS AND CELLS
56
4 EXPERIMENTAL TECHNIQUES FOR DRUG ABSORPTION MEASUREMENTS
57
41 Intestinal Rings
58
42 Isolated Intestinal Mucosal Cells
61
5 ADVANTAGES LIMITATIONS AND POTENTIAL APPLICATIONS OF RINGS AND CELLS IN QUANTITATING DRUG TRANSPORT
63
REFERENCES
64
Models of Drug Absorption in Situ and in Conscious Animals
67
2 IN SITU ABSORPTION MODELS
68
22 Cannulation of the Lumen with Blood Replacement
69
24 Simultaneous Perfusion of the Rat Small Intestine and Liver
71
3 ABSORPTION ASSESSMENT IN CONSCIOUS ANIMALS
73
31 Surgical Techniques
74
32 DATA ANALYSIS IN IN VIVO EXPERIMENTS
81
4 COMPARISON OF METHODS USED TO STUDY GASTROINTESTINAL ABSORPTION
82
Model Systems for Intestinal Lymphatic Transport Studies
85
2 METHODS
86
22 Animal Handling and Preparation
87
23 Surgical Procedures
88
24 General Experimental Protocol and Animal Monitoring
92
26 Drug and TViglyceride Analysis
94
27 Alternative Animal Models
96
3 METHODOLOGICAL DIFFERENCES IN TRANSPORT STUDIES
97
33 Anesthetized versus Conscious Models
98
34 Choice of Coadministered Lipid
99
35 Scaling Rat Lymphatic Transport Data to Higher Species
100
REFERENCES
101
Buccal Tissues and Cell Culture
103
2 METHODS
104
22 Buccal Cell Culture
107
23 In Vivo Dog Model
109
3 APPLICATIONS TO ABSORPTION AND METABOLISM
110
4 ADVANTAGES AND DISADVANTAGES COMPARED TO OTHER METHODS
111
REFERENCES
112
Isolated Hepatocytes
115
2 METHODS
116
23 Calculations of Data
117
24 Comments
118
3 ADVANTAGES AND DISADVANTAGES OVER OTHER METHODS
119
Cultured Rat Hepatocytes
121
2 METHODS
122
22 Hepatocyte Isolation and Primary Cell Culture
125
23 Overlay of Cell Cultures with Extracellular Matrix
127
3 PROPERTIES OF PRIMARY CULTURES OF RAT HEPATOCYTES
128
34 Use of Hepatocyte Cultures for in Vitro Studies
129
42 Matrix Effects
134
5 APPLICATIONS TO DRUG DEVELOPMENT AND METABOLISM
135
52 Microsomal Enzyme Induction
139
53 Drug Metabolism
143
6 ADVANTAGES AND DISADVANTAGES OF CULTURED HEPATOCYTES
144
7 APPENDIX
146
72 Procedures for Hepatocyte Isolation
148
REFERENCES
152
Isolated Perfused Liver
161
2 METHODS
163
22 Perfusate Composition and Flow Rate
167
23 Surgical Procedures
169
24 Viability Assessments
173
25 Experimental Protocols and Data Collection and Analysis
176
26 Comparison of Techniques
178
3 APPLICATIONS OF THE ISOLATED PERFUSED LIVER
179
32 Specialized Applications
182
4 ADVANTAGES AND DISADVANTAGES OF THE ISOLATED PERFUSED LIVER AS COMPARED TO OTHER MODELS
183
REFERENCES
186
Isolated Renal Brush Border and Basolateral Membrane Vesicles and Cultured Renal Cells
193
2 ISOLATED RENAL PLASMA MEMBRANE VESICLES
194
22 Materials
195
23 Procedures
196
3 CULTURED RENAL EPITHELIAL CELLS
201
32 Materials
202
4 TRANSPORT STUDIES IN MEMBRANE VESICLES AND CELLS
205
42 Driving Force Studies
206
43 Inhibition Studies
207
44 Counterflux and Transstimulation Studies
208
REFERENCES
209
Use of an Isolated Perfused Kidney to Assess Renal Clearance of Drugs Information Obtained in SteadyState and NonSteadyState Experimental Syste...
211
2 ISOLATED PERFUSED KIDNEY
212
22 Hemodynamic Properties and Viability of the IPK
214
24 Assessment of Renal Clearance in the IPK
215
26 The NonFiltering Perfused Kidney System
220
Analysis of Renal Handling of Epidermal Growth Factor Using the FK and NFK
221
3 MULTIPLE INDICATOR DILUTION METHOD
224
31 PulseInjection MID Method Using the Rat IPK
225
24 Preparation of Growth Surfaces for Brain Microvessels
245
25 Seeding of Brain Microvessels onto Growth Surfaces
246
3 EXPERIMENTAL PROTOCOLS FOR UPTAKE AND TRANSPORT STUDIES
248
33 Protein Estimation
249
4 CALCULATIONS OF DATA
250
5 PHARMACEUTICAL APPLICATIONS
251
53 Permeability Regulation
252
62 Appropriate Roles and Relationship to the BBB in Vivo
253
64 Status of Cell Line Development
254
7 CONCLUSIONS AND FUTURE PERSPECTIVES
255
Methods to Study Drug Transport in Isolated Choroid Plexus Tissue and Cultured Cells
259
12 Importance of the Choroid Plexus in Drug Delivery and Targeting to the Brain
261
14 Techniques for the Study of Drug Transport in the Choroid Plexus
262
21 Materials
263
22 Procedures
264
23 Mechanisms of Transport
266
24 Potential Problems
271
25 Calculation of Transport Parameters
272
3 CULTURED CHOROID PLEXUS EPITHELIAL CELLS
273
31 Materials
274
32 Procedures
275
33 Calculation of Transport Parameters and Flux
281
REFERENCES
282
Brain Perfusion Systems for Studies of Drug Uptake and Metabolism in the Central Nervous System
285
2 IN SITU BRAIN PERFUSION METHOD
287
22 Surgical Preparation
288
23 Perfusion Fluid
291
24 Perfusion Apparatus
293
25 Perfusion Experiment
295
26 Calculations
296
3 APPLICATIONS
299
4 ADVANTAGES AND DISADVANTAGES
302
REFERENCES
303
In Vitro Nasal Models
309
2 METHODS
310
23 Isolated Airway Epithelial Membranes
314
24 Nasal Homogenate Systems
317
3 ABSORPTION AND METABOLISM APPLICATIONS
319
4 ADVANTAGES AND DISADVANTAGES OF IN VITRO NASAL MODELS
320
REFERENCES
321
Models for Investigation of Peptide and Protein Transport across Cultured Mammalian Respiratory Epithelial Barriers
325
2 METHODS AND MATERIALS
326
21 Primary Culture of Alveolar Epithelial Cells
327
22 Primary Culture of Airway Epithelial Cells
330
3 AIRINTERFACE CULTURE
333
42 Flux Measurements of Peptides and Proteins
335
43 Metabolism of Peptides and Proteins
336
REFERENCES
339
Drug Transport across Xenopus Alveolar Epithelium in Vitro
347
2 METHODS
348
23 Electrical Parameters
349
25 Electron Microscopy
350
3 EXPERIMENTAL PROTOCOLS
351
33 Determination of TissueAssociated Radioactivity
352
34 Calculation of Data
353
5 ADVANTAGES AND DISADVANTAGES OVER OTHER METHODS
356
REFERENCES
358
In Situ and in Vivo Methods for Pulmonary Delivery
361
2 ISOLATED PERFUSED RAT LUNG MODEL IPRL
362
22 Materials and Methods
363
23 Treatment of the Data
364
32 Materials and Methods
365
33 Treatment of the Data
366
4 AEROSOL DEPOSITION MODEL
367
42 Materials and Methods
368
43 Treatment of the Data
369
5 DISCUSSION
371
REFERENCES
373
In Vitro Viable Skin Model
375
2 METHODS
376
22 Preparation of Membrane
377
23 Diffusion Cell Design
378
24 Receptor Fluid
380
25 Temperature
381
29 Measurement of Percutaneous Absorption
382
4 COMPARISON OF MODEL TO OTHER METHODS
385
Isolated Perfused Porcine Skin Flap Systems
387
2 METHODS
388
22 Isolated Perfusion Technique
390
24 Design of Percutaneous Absorption and Transdermal Drug Delivery Studies
391
25 Data Analysis
392
26 Pharmacokinetic Modeling and in Vitro to in Vivo Extrapolation
395
3 APPLICATIONS
398
32 Iontophoresis
402
4 ADVANTAGES AND DISADVANTAGES OF THE IPPSF
404
REFERENCES
405
Vaginal Epithelial Models
409
21 Materials
411
23 In Situ Model
414
24 In Vivo Model
418
25 Ovariectomized Rat Model
419
26 Metabolic Enzyme Activity Study
420
3 APPLICATIONS
421
4 ADVANTAGES AND DISADVANTAGES
422
REFERENCES
423
Ocular Epithelial Models
425
2 CHOICE OF ANIMAL MODELS
426
3 TYPES OF EXPERIMENTAL MODELS
427
32 In Vivo Models
428
4 CONCLUSIONS
432
REFERENCES
433
Index
437
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